Dopamine (DA) neurons exhibit differential neurotoxin susceptibility that may provide insight into factors protecting dopaminergic neurons from cell death. Nigrostriatal DA (NSDA), mesolimbic DA (MLDA), and hypothalamic tuberoinfundibular DA (TIDA) display disparate degrees of toxicity following exposure to toxins inhibiting mitochondrial complex I, a pattern that parallels the regional degeneration of these neuronal populations in PD. NSDA neurons are exquisitely vulnerable, while other DA neurons appear partially (MLDA) or completely (TIDA) resistant to neurotoxin exposure and degeneration in PD. The mechanisms of selective neurotoxin vulnerability in these three distinct populations of dopaminergic neurons are poorly understood. We hypothesize that region-specific neuronal expression of cytoprotective genes, rather than extraneuronal microenvironmental factors, determine the relative resistance of TIDA and MLDA hypothalamic DA neurons to the toxic effects of MPTP and to degeneration in PD. To address this hypothesis, the following specific aims are proposed: 1. To demonstrate regional differences in neurotoxin susceptibility in NSDA, MLDA, and hypothalamic TIDA neurons following chronic exposure to mitochondrial complex I inhibitors in vivo. 2. To determine if primary DA neurons corresponding to NSDA, MLDA and hypothalamic TIDA neurons have differential sensitivity to neurotoxin exposure in vitro. 3. To compare and contrast mRNA expression phenotypes in NSDA, MLDA and hypothalamic TIDA neurons in mice under basal conditions and following chronic mitochondrial complex I inhibition. 4. To compare and contrast mRNA expression phenotypes in NSDA, MLDA and hypothalamic TIDA neurons of patients with PD and from age-matched controls.